2-pyridinecarbothioamides, processes for preparation thereof

ABSTRACT

There are provided gastric antiulcer and cytoprotective substituted N-phenyl-2-pyridinecarbothioamides. The process for their production and formulation is disclosed.

This is a divisional of co-pending application Ser. No. 07/123,740 filedon Nov. 23, 1987 now U.S. Pat. No. 4,886,821.

BACKGROUND OF THE INVENTION

The present invention relates to novel 2-pyridinecarbothioamides. Moreparticularly, it relates to novel 2-pyridinecarbothioamides which haveinhibitory activity on ulcers, to processes for preparation thereof, topharmaceutical compositions comprising the same, and to the method ofusing the same therapeutically in the treatment of ulcers in humanbeings and animals.

The compounds of the present invention have the following formula:##STR1## wherein R¹ is fluorine, R² and R³ are each hydrogen orfluorine, and R⁴ is hydrogen or lower alkyl.

The closest prior art is German Patent No. 953,635 (1956) and E. A.Popova et al, Deposited Doc. 1981, SPSTL 586 Khp-D81. They disclose anumber of 2-pyridinecarbothioamides as intermediates in the preparationof therapeutics and bactericidal agents, respectively. However, thecompounds of the present invention are not exemplified in the numerousexamples contained in the two above mentioned references.

Although the mechanism of cytoprotection is not clearly defined yet,there is a suggestion that it may be partially mediated through therelease of gastric mucosal prostaglandins, (Hollander et al,Gastroenterology 86: 1114, 1984 and Tarnawski et al, Gastroenterology86: 1276, 1984). Szelenyi et al, (Gastroenterology 88: 1604, 1985) hassuggested non-prostaglandin mediated mechanisms for cytoprotection.

Activity in the ethanol induced ulcer model is an indication ofcytoprotection, regardless of the antisecretory characteristics of thedrug. Antisecretory agents, such as the H₂ receptor antagonistcimetidine and the anticholinergic agent propantheline bromide do notprotect in this model. See Robert et al, Scand. J. Gastroenterol. 19(Suppl. 101): 69-72, 1984.

The compounds of this invention have been found to possess effectivegastric and duodenal cytoprotective properties. These properties alongwith a relatively low order of toxicity, render these compounds valuableagents for treating ulcers in humans and animals.

SUMMARY OF THE INVENTION

Accordingly, one object of this invention is to provide novel2-pyridinecarbothioamides which are useful as a medicine for ulcers.

Another object of this invention is to provide processes for thepreparation of said 2-pyridinecarbothioamides.

A further object of this invention is to provide pharmaceuticalcompositions comprising, as an active agent, said2-pyridinecarbothioamides.

A still further object of this invention is to provide a method of usingsaid 2-pyridinecarbothioamides in the treatment of ulcers in humanbeings and animals.

DETAILS OF THE INVENTION

We have demonstrated that the 2-pyridinecarbothioamides of the presentinvention inhibit ethanol-induced ulcers in rats. The activity of saidcompounds in this test suggests therefore that they possess gastric andduodenal cytoprotective properties. Because of their cytoprotectivenature they may be used to treat or prevent disease states such asregional iletis, Crohn's disease, erosive gastritis, erosiveesophagitis, inflammatory bowel disease and ethanol-induced hemorrhagicerosions.

For therapeutic purposes, the compounds according to the presentinvention can be used in pharmaceutical preparations containing saidcompounds as an active ingredient, in admixture with a pharmaceuticallyacceptable carrier such as an organic or inorganic solid or liquidexcipient suitable for oral or parenteral administration. Thepharmaceutical preparations may be capsules, tablets, dragees,solutions, suspensions, emulsions, and the like. If desired, there maybe included in the above preparations auxiliary substances, stabilizingagents, wetting or emulsifying agents, buffers and other commonly usedadditives.

While the dosage of the compounds will vary depending upon the age andcondition of the patient, an average single dose of about 1 to 100 mg/kgof the compounds according to the present invention may be effective fortreating ulcer. In general, amounts between 1 to 10 mg/kg and preferablyabout 1.2 mg/kg may be administered per day.

The 2-pyridinecarbothioamides of this invention are novel and can berepresented by the following general formula (I): ##STR2## wherein R¹ isfluorine, R² and R³ are each hydrogen or fluorine, and R⁴ is hydrogen orlower alkyl containing 1 to 6 carbon atoms.

The preferred compounds of the present invention are represented by thestructural formula (I) wherein R¹ is fluorine, R² and R³ are eachhydrogen or fluorine, and R⁴ is hydrogen, methyl or ethyl.

Further preferred compounds of the present invention are represented bystructural formula (I) wherein R¹ and R² are fluorine, R³ and R⁴ arehydrogen.

The preferred compounds of the present invention are designated:

    ______________________________________                                        Example                                                                       ______________________________________                                        1     N-(3,5-difluoropheny-2-pyridinecarbothioamide;                          2     N-(2,4-difluorophenyl)-2-pyridinecarbothioamide;                        3     N-(4-fluoropheny)-2-pyridinecarbothioamide;                             4     N-(3-fluorophenyl)-2-pyridinecarbothioamide;                            5     N-(2-fluorophenyl)-2-pyridinecarbothioamide;                            6     N-(3-fluorophenyl)-N-methyl-2-pyridinecarbothioamide;                   7     N-(3,5-difluorophenyl)-N-methyl-2-pyridinecarbothioamide;               8     N-(3,5-difluorophenyl)-N-ethyl-2-pyridinecarbothioamide;                9     N-(2,6-difluorophenyl)-2-pyridinecarbothioamide;                        10    N-(2,3-difluorophenyl)-2-pyridinecarbothioamide;                        11    N-(3,4-difluorophenyl)-2-pyridinecarbothioamide;                        12    N-(2,5-difluorophenyl)-2-pyridinecarbothioamide;and                     13    N-(2,4,6-trifluorophenyl)-2-pyridinecarbothioamide.                     ______________________________________                                    

According to this invention, the compounds (I) can be prepared by thefollowing process. ##STR3## wherein R¹, R² and R³ are each as definedabove ##STR4## wherein R¹, R², R³ and R⁴ are each as defined above.

In the above and subsequent description of the present specification,suitable examples and illustrations for the various definitions to beincluded within the scope of the invention are explained in detail asfollows:

The term "lower" is intended to mean 1 to 6 carbon atoms unlessotherwise indicated.

Suitable examples of lower alkyl for R⁴ may be a straight or branchedone such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, hexyl or the like.

The process for preparing the object compounds (I) are explained indetail in the following.

PROCESS 1

The compounds (I) (R⁴ =--H) can be prepared by reacting a compound (IV)with a thiation agent (e.g. P₄ S₁₀ or Lawesson's Reagent[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide]Tetrahedron Lett., 21, 4061 (1980)).

This reaction is usually carried out in benzene, toluene, xylene orpyridine or any other solvent which does not adversely affect thereaction. The reaction is usually carried out under warming or heating.

PROCESS 2

The compounds (I) (R⁴ =lower alkyl) can be prepared by reacting acompound (V) with a thiation agent (e.g. P₄ S₁₀ or Lawesson's Reagent)under conditions closely resembling those of Process 1.

The processes for preparing the starting compounds (IV) and (V) areexplained in detail in the following. ##STR5##

The compound (IV) can be prepared by reacting a compound (II) with acompound (III) or its reactive derivative at the carboxy group. In theabove formulas R¹, R² and R³ are each as defined above.

Suitable reactive derivatives at the carboxy group of the compound (III)may include an acid halide, an acid anhydride, an ester, an activatedamide, an activated ester and the like.

Suitable examples of such reactive derivatives may be an ester such aslower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, hexylester, etc.), acid chloride, an acid azide, a mixed acid anhydride withan acid such as substituted phosphoric acid (e.g. dialkylphosphoricacid, phenylphosphoric acid, etc.), aliphatic carboxylic acid (e.g.pivalic acid, acetic acid, trichloroacetic acid, etc.) or the like, asymmetrical acid anhydride, an activated amide with imidazole, triazoleor dimethylpyrazole, an activated esther with N-hydroxysuccinimide,N-hydroxyphthalimide or 1-hydroxy-6-chlorobenzotriazole, and the like.

When a compound (III) is used in a free acid form the reaction ispreferably carried out in the presence of a conventional condensingagent such as N,N'-dicyclohexylcarbodiimide, N,N'-carbonyl-diimidazole,N-cyclohexyl-N'-morpholinoethylcarbodiimide,N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, thionyl chloride,phosphorus oxychloride, phosphorus oxybromide, oxalyl chloride, loweralkoxycarbonyl halide (e.g. ethyl chloroformate, isobutyl chloroformate,etc.), 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole, or thelike.

The reaction is usually carried out in a conventional solvent such asdioxane, chloroform, methylene chloride, ethylene chloride,tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or anyother organic solvent which does not adversely influence the reaction.

The reaction temperature is not critical, and the reaction can becarried out under cooling, at ambient temperature or under warming orheating. ##STR6## In the above formulas, R¹, R², R³ and R⁴ are each asdefined above. Suitable examples of the residue X may be halide (e.g.chloride, bromide, iodide) or the like.

This reaction is usually carried out in the presence of a base.

A suitable base may include an inorganic base such as alkali metalanhydride (e.g. sodium hydride, potassium hydride, etc.).

This reaction can be carried out in the presence of a conventionalsolvent such as aromatic hydrocarbon (e.g. benzene, toluene, xylene,etc.), N,N-dimethylformamide or any other organic solvent that does notadversely influence the reaction.

According to the invention, the compounds (V) wherein R⁴ is lower alkylcan be prepared by reductive alkylation of the amine (II) with ##STR7##and Zn(CNBH₃)₂ to produce the substituted amine ##STR8## wherein R⁵ islower alkyl containing one less carbon than R⁴ and further reacting thesubstituted amine (VII) with the reactive derivative of (III) to producethe compound (V).

In order to illustrate the usefulness of the compounds of the presentinvention they were subjected to the following pharmacological assays.

ETHANOL INDUCED CYTOTOXICITY IN RATS

The purpose of this assay is to evaluate the effectiveness of thecompounds of the present invention in preventing the formation ofgastric musosal lesions produced by ethanol. The assay is based on A.Robert et al: Gastroenterology, 77: 433-443, 1979.

Male Sprague-Dawley rats weighing between 120-150 grams were fasted for24 hours prior to the experiment (water ad libitum). At least two hoursbefore dosing, the animals were placed in individual cages with wiregrid bottoms and denied access to water.

Drug Preparation and Administration

Ethanol was administered orally at 1 mL per animal. The compounds of thepresent invention were dissolved in water or suspended in water with0.5% carboxymethylcellulose and administered orally at a dose based onan appropriate standard giving ED₅₀ to ED₇₅ response of cytoprotectiveactivity.

Methodological Detials

The rats were randomly divided into groups of equal number, ordinarily10 to a group. The rates were weighed and the individual weights wererecorded. Exactly 1 hour (4 hours in the case of Example 5) prior to theadministration of ethanol, the screening group was treated with thecompounds of the present invention, and the control group with thevehicle. One hour after administering the ethanol the animals weresacrificed by cervical dislocation. The stomachs were removed, cut alongthe greater curvature and cleansed of all debris with tap water. Thestomachs were set aside and kept moist with saline until the lesionswere scored.

Sample Analysis

Macroscopic lesions on the gastric mucosa were numerically graded. Thefinal grade assigned a stomach was the sum of all the grades.

    ______________________________________                                                  Description                                                         Grade     (Approximate length of lesion)                                      ______________________________________                                        0         no lesion                                                           1         2 mm or less                                                        2         4 mm                                                                3         6 mm                                                                ______________________________________                                    

Streaks longer than 6 mm are graded in multiples of 2 mm.

Interpretation of Data

The degree of cytotoxicity occurring in each group is represented as themean±S.E.M.

Presentation of Results and Criteria for Activity

The mean of each treatment group was compared to the control group andexpressed as the % inhibition of lesion formation.

    ______________________________________                                        Example                                                                              % Inhibition                                                                             Dose mg/kg ED.sub.50 mg/kg                                                                        m.p. °C.                         ______________________________________                                        1      --         --         1.2      140-142                                 2      --         --         4.8      124-129                                 3      --         --         2.5      82-85                                   4      --         --         1.0      72-76                                   5      69         100        --       94-97                                   6      31         10         --       100-103                                 7      40         25         --       131-134                                 8      13         10         --        99-101                                 9      --         --          0.38    138-140                                 10     --         --         1.0      89-90                                   11     --         --         1.6       98-100                                 12     --         --         6.2      141-143                                 13     --         --         0.4      160-163                                 ______________________________________                                    

STRESS-INDUCED GASTRIC ULCERS IN RATS

The purpose of this assay is to evaluate the effectiveness of thecompounds of the present invention in preventing stress induced ulcers.

Male rats (280-380 g) were fasted for 18 hours (water available adlibitum) prior to use in experiments. Eight to twelve rats were used pergroup.

Drug Preparation and Administration

Drug solutions or suspensions were prepared in physiological salinesolution. Suspensions were prepared with the aid of 0.5%carboxymethylcellulose in physiological saline solution. Drugs wereadministered orally or parenterally at predetermined intervals (usually15 to 45 minutes) prior to stress.

Methodological Details

This test procedure is according to the method of Senay et al, Proc.Soc. Exp. Biol. Med. 124, 1221 (1967), modified to produce a moreconsistent ulcer incidence. After drug administration, the rats wereimmobilized in metallic restrainers and placed in a cold room at 4°-5°C. for 3 hours before they were killed by cervical dislocation. Each ratwas given 20 mg of sodium taurocholate p.o. immediately before placingit in the restrainer. After killing the rats, the stomachs were excisedand examined. Macroscopic ulcers were subjectively assigned a grade from1 to 3 on the basis of increasing size. The number of ulcers in eachsize category was determined and multiplied by the respective grade; theaddition of the resultant values gave the cumulative ulcer score. Theaverage cumulative ulcer score of each treatment group was compared tothat of the control group and the percent inhibition of ulcer formationwas calculated. When the responses obtained were directly proportionalto the doses employed, ED₅₀ values were determined from thedose-response curves obtained.

    ______________________________________                                                    Stress Induced                                                    Example     Ulcer ED.sub.50 mg/kg                                             ______________________________________                                        1           0.9                                                               2           38.0                                                              3           3.8                                                               9           1.8                                                               10          0.9                                                               ______________________________________                                    

The following preparations and examples are given for the purpose ofillustrating the present invention.

EXAMPLE 1 N-(3,5-Difluorophenyl)-2-pyridinecarbothioamide (I,R¹ =3-F, R²=5-F, R³ =--H, R⁴ =--H)

Step (1) Preparation of N-(3,5-Difluorophenyl)-2-pyridinecarboxamide

Picolinic acid (13.0 g, 106 mmol) was added to a solution of1,1'-carbonyldiimidazole (17.11 g, 106 mmol) in dry dimethylformamide(100 mL) and the reaction stirred for 1 hour, before introduction of3,5-difluoroaniline (15.0 g, 116 mmol). After 3 days, the reactionmixture was poured into saturated sodium bicarbonate solution (1 L) andextracted with ether (2×500 mL). The organic layers were dried andconcentrated to give a solid, which was recrystallized from a mixture ofether and petroleum ether to giveN-(3,5-difluorophenyl)-2-pyridinecarboxamide (17.15 g, 69%) m.p.111°-113° C.

Step (2) Preparation of N-(3,5-Difluorophenyl)-2-pyridinecarbothioamide

N-(3,5-Difluorophenyl)-2-pyridinecarboxamide (7.00 g, 29.9 mmol) wastreated with Lawesson's reagent (6.28 g, 15.5 mmol) in toluene (90 mL)at reflux temperature for 4 hours. The solvent was removed, and theresidue was dissolved in dichloromethane, preadsorbed onto silica gel,and flash chromatographed (300 g of silica gel eluted with 10% ethylacetate in petroleum ether). Recrystallization from a mixture of ethylacetate and hexane affordedN-(3,5-difluorophenyl)-2-pyridinecarbothioamide (3.58 g, 48%) as ayellow solid, m.p. 140°-142° C. Overall yield 33%.

¹ H NMR (CDCl₃, 400 MHz): δ10.86 (br s, NH), 8.75 (d, J=8 Hz, 1H), 8.55(br d, J=4.5 Hz, 1H), 7.90 (t of d, J=8 and 1.5 Hz, 1H), 7.83 (d of d,J=8.5 and 2 Hz, 2H), 7.52-7.49 (m, 1H), 6.73 (t of t, J=8.5 and 12 Hz,1H)

UV λ_(max) (CH₃ OH): 338 mm (ε9,380), 284.5 (14,500), 235 (15,400)

MS m/z (relative intensity): 250 (M⁺, 81), 249 (68), 217 (100), 79 (35),78 (94)

Anal. Calcd. for C₁₂ H₈ F₂ N₂ S: C, 57.59; H, 3.22; N, 11.20%. Found: C,57.88; H, 3.33; N, 11.56%.

EXAMPLE 2 N-(2,4-Difluorphenyl)-2-pyridinecarbothioamide (I, R¹ =2-F, R²=4-F, R³ =--H, R⁴ =--H)

Step (1) Preparation of N-(2,4-Difluorophenyl)-2-pyridinecarboxamide

Picolinic acid (10.0 g, 81 mmol) was added to a solution of1,1'-carbonyldiimidazole (13,13 g, 81 mmol) in dimethylformamide (80 mL)and the reaction mixture was stirred for 1 hour before introduction of2,4-difluoroaniline (9.06 mL, 89 mmol). After 24 hours, the reactionmixture was poured into saturated sodium bicarbonate solution, extractedinto ether, dried, concentrated, and recrystallized using a mixture ofether and petroleum ether to yieldN-(2,4-difluorophenyl)-2-pyridine-carboxamide as a white solid (14.37 g,76.0%) m.p. 90.5°-95° C.

¹ H NMR (CDCl₃, 200 MHz): δ10.21 (br s, NH), 8.63 (br d, J=5 Hz, 1H),8.6-8.4 (m, 1H), 8.27 (d, J=8 Hz, 1H), 7.92 (t, J=8 Hz, 1H), 7.50 (d ofd, J=8 and 5 Hz, 1H), 7.0-6.8 (m, 2H)

Step (2) Preparation of N-(2,4-Difluorophenyl)-2-pyridinecarbothioamide

Lawesson's reagent (29.8 g, 74 mmol) andN-(2,4-difluorophenyl)-2-pyridinecarboxamide (14.37 g, 61 mmol) werecombined in toluene (185 mL) and refluxed for 3 hours. After evaporationof the solvent, the residue was dissolved in dichloromethane,preadsorbed on silica gel, and flash chromatographed (eluted with 2%acetate in petroleum ether) to provideN-(2,4-difluorophenyl)-2-pyridinecarbothioamide as a yellow solid (14.45g, 94%) m.p. 124°-129° C.

¹ H NMR (CDCl₃, 400 MHz): δ10.89 (br s, NH), 8.92 (m, 1H), 8.75 (d, J=8Hz, 1H), 8.57 (br d, J=5 Hz, 1H), 7.89 (br t, J=8 Hz, 1H), 7.49 (d of d,J=8 and 5 Hz, 1H), 7.02-6.94 (m, 2H)

MS m/z (relative intensity): 250 (M⁺, 62), 231 (76), 230 (36), 217 (79),78 (100)

Anal. Calcd. for C₁₂ H₈ F₂ N₂ S: C, 57.59; H, 3.22; N, 11.19%. Found: C,57.96; H, 3.41; N, 11.15%.

EXAMPLE 3 N-(4-Fluorophenyl)-2-pyridinecarbothioamide (I, R¹ =4-F, R²=--H, R³ =--H, R⁴ =--H)

Step (1) Preparation of N-(4-Fluorophenyl)-2-pyridinecarboxamide

An anhydrous solution of 1,1'-carbonyldiimidazole (13.13 g, 81 mmol) indimethylformamide (80 mL) was treated with picolinic acid (10.0 g, 81mmol), and after 1 hour 4-fluoroaniline (8.46 mL, 89 mmol) wasintroduced. After 27 hours the reaction mixture was poured intosaturated sodium bicarbonate solution (900 mL) and ether (400 mL). Theaqueous layer was extracted again with ether (3×400 mL) and the ethereallayers were dried and concentrated. The crude solid residue wasrecrystallized from a mixture of ether and petroleum ether to yieldN-(4-fluorophenyl)-2-pyridinecarboxamide (11.6 g, 66%) as beigecrystals, m.p. 100°-103° C.

¹ H NMR (CDCl₃ 200 MHz): δ10.0 (br s, NH), 8.61 (br d, J=4 Hz, 1H), 8.30(d, J=8 Hz, 1H), 7.92 (br t, J=8 Hz, 1H), 7.77 (d, J=9 Hz, 1H), 7.73 (d,J=9 Hz, 1H), 7.55-7.45 (m, 1H), 7.10 (d, J=9 Hz, 1H), 7.04 (d, J=9 Hz,1H)

IR (KBr, cm⁻¹): 3340, 1680

MS m/z (relative intensity): 216 (M⁺, 88), 106 (30), 79 (100), 78 (100)

Step (2) Preparation of N-(4-Fluorophenyl)-2-pyridinecarbothioamide

N-(4-fluorophenyl)-2-pyridinecarboxamide (11.47 g, 53.0 mmol) andLawesson's reagent (25.75 g, 63.7 mmol) were refluxed in toluene for 6.5hours, preadsorbed onto silica gel, and flash chromatographed (500 g ofsilica gel eluted with 15% ethyl acetate in petroleum ether) affordingN-(4-fluorophenyl)-2-pyridinecarbothioamide as a yellow solid (6.60 g,54%) m.p. 82°-85° C.

¹ H NMR (DMSO, 400 MHz): δ10.75 (br s, NH), 8.68 (br d, J=4 Hz, 1H),8.53 (d, J=8 Hz, 1H), 8.04 (t of d, J=8 and 2 Hz, 1H), 7.98-7.91 (m,2H), 7.68-7.64 (m, 1H) 7.33-7.26 (m, 2H)

UV λ_(max) (CH₃ OH): 339 mm (ε7,100), 282.5 (13,130), 232.5 (14,300)

MS m/z (relative intensity): 232 (M⁺, 77), 231 (57), 199 (100), 78 (74)

Anal. Calcd. for C₁₂ H₉ FN₂ S: C, 62.05; H, 3.90; H, 12.06%. Found: C,62.21; H, 3.88; N, 12.26%.

EXAMPLE 4 N-(3-Fluorophenyl)-2-pyridinecarbothioamide (I, R¹ =3-F, R²=--H, R³ =--H, R⁴ =--H)

Step (1) Preparation of N-(3-Fluorophenyl-2-pyridinecarboxamide

Picolinic acid (10.0 g, 81 mmol) was added to a solution of1,1'-carbonyldiimidazole (13.13 g, 81 mmol) in dimethylformamide (80 mL)to form the corresponding imidazolide, which after 1 hour was reactedwith 3-fluoroaniline (8.55 mL, 89 mmol) at room temperature. After 21hours, the reaction mixture was poured into saturated sodium carbonatesolution (900 mL), extracted into diethyl ether (3×400 mL), dried,concentrated, and recrystallized from a mixture of ether and petroleumether to afford N-(3-fluorophenyl)-2-pyridinecarboxamide as beigecrystals (13.0 g, 74%) m.p. 74°-78° C.

¹ H NMR (CDCl₃, 200 MHz): δ10.06 (br s, NH), 8.60 (br d, J=5 Hz, 1H),8.29 (d, J=8 Hz, 1H), 7.90 (br t, J=8 Hz, 1H), 7.74 (br d, J=10 Hz, 1H),7.6-7.3 (m, 3H), 6.83 (br t, J=8 Hz, 1H)

Step (2) Preparation of N-(3-Fluorophenyl)-2-pyridinecarbothioamide

N-(3-Fluorophenyl)-2-pyridinecarboxamide (13.0 g, 60 mmol) andLawesson's reagent (29.2 g, 72 mmol) were refluxed in toluene (180 mL)for 3 hours. The residue obtained after evaporating the solvent wasflash chromatographed on silica gel (eluted with 2% ethyl acetate inpetroleum ether) and then recrystallized from a mixture ofdichloromethane and hexanes to yield aN-(3-fluorophenyl)-2-pyridinecarbothioamide as a yellow solid (6.75 g,48%) m.p. 72°-76° C.

¹ H NMR (CDCl₃, 400 MHz): δ10.88 (br s, NH), 8.77 (d, J=8 Hz, 1H), 8.54(br d, J=5 Hz, 1H), 8.19 (d of t, J=8 and 2 Hz, 1H), 7.88 (t of d, J=8and 2 Hz, 1H), 7.68 (d of d, J=8 and 2 Hz, 1H), 7.48 (d of d of d, J=8,5and 1 Hz, 1H), 7.42-7.36 (m, 1H), 6.97 (t of d, J=8 and 2.5 Hz, 1H)

MS m/z (relative intensity): 232 (M⁺, 90), 231 (84), 199 (100), 169(74), 78 (95)

Anal. Calcd. for C₁₂ H₉ FN₂ S: C, 61.99; H, 3.87; N, 12.05%. Found: C,62.01; H, 4.01; N, 11.98%.

EXAMPLE 5 N-(2-Fluorophenyl)-2-pyridinecarbothioamide (I, R¹ =2-F, R²=--H, R³ =--H, R⁴ =--H)

Step (1) Preparation of N-(2-Fluorophenyl)-2-pyridinecarboxamide

Picolinic acid (10.0 g, 81 mmol) was added to a solution of1,1'-carbonyldiimidazole (13.18 g, 81 mmol) in anhydrousdimethylformamide (80 mL), followed by the addition of 2-fluoroaniline(8.6 mL, 89 mmol) 1 hour later. The reaction mixture was poured intosaturated sodium bicarbonate solution (900 mL) after 26 hours, andextracted with ether (3×400 mL). The dried organic material wasconcentrated in vacuo and recrystallized from a mixture of ether andpetroleum ether to yield N-(2-fluorophenyl)-2-pyridinecarboxamide as awhite solid (11.81 g) m.p. 112°-115° C.

Step (2) Preparation of N-(2-Fluorophenyl)-2-pyridinecarbothioamide

N-(2-fluorophenyl)-2-pyridinecarboxamide (11.81 g, 55 mmol) was reactedwith Lawesson's reagent (26.04 g, 64 mmol) in toluene (160 mL) at refluxtemperature for 5 hours. The solution was preadsorbed onto silica geland flash chromatographed (eluted with 2.5% ethyl acetate in petroleumether) to give N-(2-fluorophenyl)-2-pyridinecarbothioamide as a yellowsolid (7.26 g, 39%) m.p. 94°-97° C.

¹ H NMR (CDCl₃, 400 MHz): δ10.74 (br s, NH), 9.07-9.03 (m, 1H), 8.77 (d,J=8 Hz, 1H), 8.58 (br d, J=5.5 Hz, 1H), 7.89 (t of d, J=8 and 2 Hz, 1H),7.50-7.47 (m, 1H), 7.27-7.19 (m, 3H)

Anal. Calcd. for C₁₂ H₉ FN₂ S: C, 62.05; H, 390; N, 12.06%. Found: C,61.78; H, 4.17; N, 12.37%.

EXAMPLE 6 N-(3-Fluorophenyl)-N-methyl-2-pyridinecarbothioamide (I, R¹=3-F, R² =--H, R³ =--H, R⁴ =--CH₃)

Step (1) Preparation ofN-(3-Fluorophenyl)-N-methyl-2-pyridinecarboxamide.

To a suspension of 60% sodium hydride (1.76 g, 44 mmol) in drydimethylformamide (50 mL) under nitrogen was added dropwise a solutionof N-(3-fluorophenyl)-2-pyridinecarboxamide (6.87 g, 32 mmol), preparedby the process of Example 4, Step 1, in dimethylformamide (25 mL) over30 minutes. After 30 minutes more, iodomethane (3.58 mL, 57 mmol) wasadded. The reaction mixture was quenched with water (500 mL), extractedwith ether (3×400 mL) and further extracted with ethyl acetate (300 mL).After washing with brine the ethyl acetate layer was combined with theother organic extracts, which were dried and preadsorbed onto silicagel. Flash chromatography (250 g of silica gel gradient elution with20-50% ethyl acetate in petroleum ether) was utilized to affordN-(3-fluorophenyl)-N-methyl-2-pyridinecarboxamide (3.81 g, 52%) m.p.75°-78° C.

¹ H NMR (CDCl₃, 400 MHz): δ8.33 (br d, J=5 Hz, 1H), 7.64 (br t, J=7.5Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 7.18-7.11 (m, 2H), 6.84-6.80 (m, 3H),3.49 (s, 3H)

IR (KBr, cm⁻¹): 1640

MS m/z (relative intensity: 230 (M⁺, 78), 124 (67), 107 (28), 79 (83),78 (100)

Step (2) Preparation ofN-(3-Fluorophenyl)-N-methyl-2-pyridinecarbothioamide

Lawesson's reagent (3.20 g, 7.9 mmol) andN-(3-fluorophenyl)-N-methyl-2-pyridinecarboxamide (3.51 g, 15.2 mmol)were heated to reflux in toluene (45 mL) under nitrogen for 2 hours. Theresidue, after evaporation of the solvent, was dissolved indichloromethane, preadsorbed onto silica gel, and flash chromatographed(250 g of silica gel eluted with 10% ethyl acetate in petroleum ether)to yield N-(3-fluorophenyl)-N-methyl-2-pyridinecarbothioamide, as ayellow solid (1.70 g, 45%), m.p. 100°-103° C.

¹ H NMR (DMSO, 499 MHz): δ8.15 (br d, J=4.5 Hz, 1H), 7.67 (t of d, J=8and 1.5 Hz, 1H), 7.50 (d, J=8 Hz, 1H), 7.24-7.10 (m, 3H), 7.02-6.94 (m,2H), 3.84 (s, 3H)

MS m/z (relative intensity): 246 (M⁺, 32), 123 (100), 119 (70), 78 (30)

Anal. Calcd. for C₁₃ H₁₁ FN₂ S: C, 63.39; H, 4.50; N, 11.37%. Found: C,63.41; H, 4.54; N, 11.38%.

EXAMPLE 7 N-(3,5-Difluorophenyl)-N-methyl-2-pyridinecarbothioamide (I,R¹ =3-F, R² =5-F, R³ =--H, R⁴ =--CH₃)

To a suspension of 80% sodium hydride (1.22 g, 41 mmol) in anhydrousdimethylformamide (90 mL), was added dropwise a solution ofN-(3,5-difluorophenyl)-2-pyridinecarboxamide, prepared by a process ofExample 1, difluorophenyl)-2-pyridinecarboxamide, prepared by theprocess of Example 1, Step 1 (8.71 g, 37 mmol) in dimethylformamide (30mL). The reaction mixture was warmed to 65° C. for 1 hour and thentreated with iodomethane (2.60 mL, 42 mmol) at room temperature. After2.5 hours the reaction mixture was poured into water (500 mL) andextracted with ethyl acetate (2×300 mL). The combined organic layerswere washed with 75% brine, dried, preabsorbed onto silica gel, andflash chromatographed (300 g, elution with 40% ethyl acetate inpetroleum ether) to yield pureN-(3,5-difluorophenyl)-N-methyl-2-pyridinecarboxamide (5.16 g, 21 mmol,56%, m.p. 102°-104° C.), which was reacted with Lawesson's reagent (4.36g, 11 mmol) in anhydrous toluene (65 mL) at reflux temperature for 1.5hours. The toluene was evaporated and the residue was dissolved indichloromethane, preadsorbed onto silica gel, flash chromatographed (300g, elution with 10% ethyl acetate in petroleum ether), andrecrystallized from ethyl acetate in petroleum ether to afford a yellowsolid (2.36 g, 24%), m.p. 131°-134° C.

¹ H NMR (CDCl₃, 400 MHz): δ8.25 (br s, 1H), 7.60 (br s, 2H), 7.09 (br s,1H), 6.63 (br s, 3H), 3.89 (br s, 3H)

IR (KBr, cm⁻¹): 1600, 1110

MS m/z: 264 (M⁺, 19), 123 (100), 119 (41), 78 (26)

Anal. Calcd. for C₁₃ H₁₀ F₂ N₂ S: C, 59.07; H, 3.81; N, 10.60%. Found:C, 59.17; H, 4.04; N, 10.73%.

EXAMPLE 8 N-(3,5-Difluorophenyl)-N-ethyl-2-pyridinecarbothioamide (I, R¹=3-F, R² =5-F, R³ =--H, R⁴ =--C₂ H₅)

Step (1) Preparation ofN-(3,5-Difluorophenyl)-N-ethyl-2-pyridinecarboxamide

To a solution of 3,5-difluoroaniline (4.79 g, 37.1 mmol) in methanol(100 mL) at 0° C. under nitrogen, was added acetaldehyde (2.5 mL, 44.5mmol). After 15 minutes of stirring, a 0.5M solution of zinccyanoborohydride in methanol (90 mL, 45 mmol) was introduced. The icebath was removed after 15 minutes and the reaction mixture was stirredat room temperature for 2.5 hours and filtered through celite. Methanolwas removed and the residue was dissolved in methylene chloride (400mL), washed with water (2×200 mL) and brine (400 mL), dried overmagnesium sulfate, and concentrated to give a colorless liquid (5.11 g,32.5 mmol, 88%). The aniline was dissolved in dry methylene chloride(200 mL) and cooled to 0° C. Triethylamine (14 mL, 97.5 mmol) andpicolinic acid chloride hydrochloride (6.20 g, 35.8 mmol) were added tothe reaction mixture successively. After stirring for 1 hour at 0° C.,the reaction mixture was poured into water (1 L), basified using 1Nsodium hydroxide solution, and extracted with methylene chloride (3×300mL). The organic layer was washed with brine, dried over magnesiumsulfate, and preadsorbed onto silica gel. Flash chromatogaphy (3 in,elution with 5% methanol in methylene chloride) afforded the amide (5.2g), which was recrystallized from ethyl acetate in petroleum ether togive a pure tan solid (4.0 g, 41%), m.p. 99°-101° C.

¹ H NMR (CDCl₃, 400 MHz): δ8.36 (br d, J=4 Hz, 1H), 7.69 (t of d, J=8and 2 Hz, 1H, 7.59 (d, J=8 Hz, 1H), 7.21 (m, 1H), 6.64-6.60 (m, 3H),3.97 (q, J=7 Hz, 2H), 1.25 (t, J=7 Hz, 3H)

MS (m/z): 262 (M⁺, 29), 156 (100), 140 (29), 113 (30), 106 (18), 79(61), 78 (91)

Step (2) Preparation ofN-(3,5-Difluorophenyl)-N-ethyl-2-pyridinecarbothioamide

N-(3,5-Difluorophenyl-N-ethyl-2-pyridinecarboxamide (4.00 g, 15.3 mmol)was dissolved in anhydrous toluene (100 mL) and treated with Lawesson'sreagent (6.20 g, 15.3 mmol). The reaction mixture was refluxed for 1.5hours, cooled, and preadsorbed onto silica gel. Flash chromatography (3in, elution with 5% ethyl acetate in petroleum ether) gave the thioamidewhich was recrystallized from ethyl acetate in petroleum ether to afforda pure yellow solid (1.87 g, 44%), m.p. 111°-113° C.

¹ H NMR (CDCl₃, 400 MHz): δ8.24 (br s, 1H), 7.58 (m, 1H), 7.52 (m, 1H),7.05 (br s, 1H), 6.63 (m, 3H), 4.48 (m, 2H), 1.37 (m, 3H).

MS (m/z): 278 (M⁺, 16), 123 (100), 78 (22)

IR (KBr, cm⁻¹): 1410

Anal. Calcd. for C₁₄ H₁₂ F₂ N₂ S: C, 60.42; H, 4.35; N, 10.06%. Found:C, 60.62; H, 4.21; N, 10.03%.

EXAMPLE 9 N-(2,6-Difluorophenyl)-2-pyridinecarbothioamide (I, R¹ =2-F,R² =6-F, R³ =--H, R⁴ =--H)

To a 0° C. solution of 2,6-difluoroaniline (6.80 mL, 63.5 mmol) in drymethylene chloride (200 mL), triethylamine (26 mL, 186.5 mmol) wasadded, followed by picolinic acid chloride hydrochloride (11.3 g, 63.5mmol). The reaction mixture was brought to room temperature and stirredfor 1.5 hours and then poured into water (1 L). The resulting mixturewas basified with 2.5N sodium hydroxide solution and extracted withmethylene chloride. The organic layer was washed with brine, dried overmagnesium sulfate and concentrated to give a beige solid (9.63 g, 41.2mmol, 65%, m.p. 95°-98° C.). The amide was treated with Lawesson'sreagent (14.85 g, 37 mmol) in anhydrous toluene (120 mL) at refluxtemperature for 2 hours. The reaction mixture was adsorbed onto silicagel and flush chromatographed (4 in, elution with 5% ethyl acetate inpetroleum ether) to give light yellow crystals (5.91 g, 57%, or 37%overall yield), m.p. 138°-140° C.

¹ H NMR (CDCl₃, 400 MHz): δ11.1 (br s, NH), 8.74 (d, J=8 Hz, 1H), 8.56(d, J=4 Hz, 1H), 7.88 (t of d, J=8 and 2 Hz, 1H), 7.49 (m, 1H), 7.35 (m,1H), 7.04 (t,J=9 Hz, 2H)

IR (KBr, cm⁻¹): 3220, 1510

MS (m/z): 250 (M⁺, 80), 231 (100), 217 (74), 78 (94)

Anal. Calcd. for C₁₂ H₈ F₂ N₂ S: C, 57.59; H, 3.22; N, 11.19%. Found: C,57.76; H, 3.30; N, 10.84%.

We claim:
 1. The process for producing compounds of structural formula(I) ##STR9## wherein R¹ is fluorine, R² and R³ are each hydrogen orfluorine, and R⁴ is hydrogen which comprises(a) activating the compoundof structure ##STR10## with 1,1'-carbonyldiimidazole to form theactivated imidazolide ##STR11## (b) reacting said activated imidazolidewith the substituted aniline ##STR12## wherein R¹, R² and R³ are asdefined above to form the amide ##STR13## (c) and reacting said amide(IV) with Lawesson's Reagent to form the desired product (I).
 2. Theprocess according to claim 1 for producing compounds of structure (I)##STR14## wherein R¹ is fluorine, R² and R³ are each hydrogen orfluorine and R⁴ is lower alkyl containing 1 to 6 carbon atoms whichcomprises(a) reacting the amide of structure (IV) ##STR15## wherein R¹,R² and R³ are as defined above with lower alkyl iodide in the presenceof a strong base to form the N-lower alkyl amide of structure (V)##STR16## (b) and reacting said N-lower alkyl amide with Lawesson'sReagent to form the desired product (I).
 3. The process for producingcompounds of structural formula (I) ##STR17## wherein R¹ is fluorine, R²and R³ are each hydrogen or fluorine and R⁴ is lower alkyl containing 1to 6 carbon atoms which comprises(a) reacting the amine of structure(II) ##STR18## wherein R¹, R² and R³ are as defined above withZn(CNBH₃)₂ and the aldehyde ##STR19## wherein R⁵ is lower alkylcontaining one less carbon than R⁴ to form the substituted amine ofstructure (VII) ##STR20## (b) reacting said substituted amine with acidchloride derivative of (III) of structure ##STR21## to form the N-loweralkyl amide of structure (V) ##STR22## wherein R¹, R², R³ and R⁴ are asdefined above, and (c) reacting said N-lower alkyl amide with Lawesson'sreagent to form the desired product (I).